Format

Send to

Choose Destination
Sci Transl Med. 2019 May 1;11(490). pii: eaat8462. doi: 10.1126/scitranslmed.aat8462.

Aβ and tau prion-like activities decline with longevity in the Alzheimer's disease human brain.

Author information

1
Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
2
Daiichi Sankyo Co. Ltd., Tokyo 140-8710, Japan.
3
Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA. carlo.condello@ucsf.edu stanley.prusiner@ucsf.edu.
4
Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
5
AC Immune SA, EPFL Innovation Park, Building B, 1015 Lausanne, Switzerland.
6
NeuRA and School of Medical Sciences, University of New South Wales, and Brain and Mind Centre, University of Sydney, Sydney, NSW 2052, Australia.
7
Leiden University Medical Center, Leiden, Netherlands.
8
Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, 751 85 Uppsala, Sweden.
9
Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Solna, Sweden.
10
Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden.
11
Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA.
12
Department of Neurology, University of Washington, Seattle, WA 98195, USA.
13
Department of Neuropathology, University of Washington School of Medicine, Seattle, WA 98195, USA.
14
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
15
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
16
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.

Abstract

The hallmarks of Alzheimer's disease (AD) are the accumulation of Aβ plaques and neurofibrillary tangles composed of hyperphosphorylated tau. We developed sensitive cellular assays using human embryonic kidney-293T cells to quantify intracellular self-propagating conformers of Aβ in brain samples from patients with AD or other neurodegenerative diseases. Postmortem brain tissue from patients with AD had measurable amounts of pathological Aβ conformers. Individuals over 80 years of age had the lowest amounts of prion-like Aβ and phosphorylated tau. Unexpectedly, the longevity-dependent decrease in self-propagating tau conformers occurred in spite of increasing amounts of total insoluble tau. When corrected for the abundance of insoluble tau, the ability of postmortem AD brain homogenates to induce misfolded tau in the cellular assays showed an exponential decrease with longevity, with a half-life of about one decade over the age range of 37 to 99 years. Thus, our findings demonstrate an inverse correlation between longevity in patients with AD and the abundance of pathological tau conformers. Our cellular assays can be applied to patient selection for clinical studies and the development of new drugs and diagnostics for AD.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center